Predicting the risk of recurrent venous thromboembolism: Impact and therapeutic consequences of inherited thrombophilia.

BACKGROUND: Over the past decades, thrombophilia testing in patients with venous thrombo-embolism has increased tremendously. However, the role of inherited thrombophilie in prediction the risk of recurrence remains controversial. Consequently, it is still unclear whether thrombophilia testing influences decisions regarding duration of anticoagulation in clinical practices. The aim of this study was to evaluate the impact if inherited thrombophilia on venous thrombosis treatment decisions and on predicting the risk of recurrence. METHODS: A retrospective longitudinal study (January 2011-Decembre 2016) including 131 patients with confirmed venous thrombo-embolism referred to the hematology laboratory from the internal medicine department for inherited thrombophilia screening was carried out. RESULTS: The mean age patients was 39.4 years and the sex ratio (M/F) was 0.61. Inherited thrombophilia was confirmed in 27.5% of patients. A long term anticoagulation was decided in 46.9% of patients with thrombophilia. There was no significant difference in the duration of anticoagulation between patients with or without thrombophilia. Thrombosis recurrence was recorded in 16 (17%) patients. The 24 years cumulative incidence of recurrence was 19% in patients with thrombophilia and 17% in those without (plog Rank= 0.6). Inherited thrombophilia was not associated with increased risk of recurrence after treatment withdrawal (Hazard ratio=1.31 IC (0.47-3.63); P=0.6). CONCLUSION: In clinical practice, inherited thrombophilia did not influence anticoagulation duration and was not associated with a higher venous thrombosis risk of recurrence. It seems to be less relevant for decision making than presumed.

[Epidemiology of uveitis in the Tunis area]. / Profil épidémiologique des uvéites dans la région de Tunis.

PURPOSE: To identify the epidemiological characteristics and the most common etiologies of uveitis in the Tunis area. METHODS: Medical records for all uveitis patients seen from September 2003 through October 2009 were included. RESULTS: A total of 424 patients (596 eyes) were included. The mean age at onset of uveitis was 36 years, and the male-to-female ratio was 0.66. Uveitis was unilateral in 56.4%. Anterior uveitis was most common (48%), followed by panuveitis (33.6%), posterior uveitis (13.3%), and intermediate uveitis (5%). The most common causes were Behçet disease (14.7%), toxoplasmosis (10.2%), Vogt-Koyanagi-Harada (VKH) syndrome (3.7%) and sarcoidosis (3.3%). Retinal vasculitis was found in 20%. Behçet disease was the most common cause of chronic uveitis. The most common complications were cataract (21.6%), ocular hypertension (12%) and macular edema (5.6%). CONCLUSION: In our study, the most common causes of uveitis were Behçet disease, toxoplasmosis, VKH syndrome and sarcoidosis.

Toll-like-receptor gene polymorphisms in a Tunisian population with Behçet's disease.

OBJECTIVE: The manifestations of BD are considered to have developed as a result of immunological dysfunction, which is suggested to be induced by microbial pathogens. The Toll-like receptor (TLR) genes were known to be associated with a variety of infectious diseases due to their central role in both innate and adaptive immunity. In this report, we investigated the possible association between BD patients and genetic variations within the TLR 2, 4 and 9 genes in a Tunisian population. PATIENTS AND METHODS: 135 Tunisian BD patients and 159 healthy blood donors from the same geographical area were genotyped by polymerase chain reaction for the TLR polymorphisms. RESULTS: Among the TLR polymorphisms, only the distribution of TLR9 1486 T/C genotype (p=0.07; chi2=3.30; OR=1.54; 95% CI=0.94-2.51) and allele (p=0.08; chi2=2.91; OR=1.34; 95% CI=0.94-1.92) frequencies was different between BD patients and healthy controls, but did not reach statistical significance. For the TLR9 1237 T/C, the distribution of genotypes and alleles were not significantly different comparing total patients with controls. There were no associations between the studied polymorphisms and the main clinical manifestations of BD. The G, T and A allele of the TLR4 1896 A/G, TLR4 11196 C/T and TLR2 12408 G/A polymorphisms were uncommon and absent in the Tunisian population. CONCLUSION: Our results showed that SNPs in the TLR2, 4 and 9 genes were not significantly associated with susceptibility to BD.

Serum BAFF levels and skin mRNA expression in patients with Behçet's disease.

OBJECTIVE: Serum levels of the B-cell activating factor in the tumor necrosis factor family (BAFF), a potent contributor to B-cell survival, are elevated in patients with systemic autoimmune diseases. The objective of this study was to determine serum BAFF levels and to link the results to the clinical features in patients with skin manifestations. METHODS: Serum BAFF levels were examined by an enzyme-linked immunosorbent assay (ELISA) in 42 patients with BD (16 with active disease), 20 healthy controls, and in 20 patients with systemic lupus erythematosus (SLE) and 15 patients with multiple sclerosis (MS), who served as the disease control groups. Expression of BAFF messenger RNA (mRNA) in the skin was quantified by a real-time reverse transcription-polymerase chain reaction; the expression of BAFF receptor (BAFF-R) on CD19+ B cells was assessed by flow cytometry; and ELISA was used to evaluate the production of IgG, interleukin-6 (IL-6) and IL-10 by isolated B cells. RESULTS: Serum BAFF levels were elevated in patients with active BD compared to the healthy controls, and correlated positively with the extent of skin lesions. Disease remission was accompanied by decreased BAFF levels. SLE patients had the highest serum BAFF levels. Skin biopsies showed BAFF mRNA expression to be up-regulated in active BD patients. BAFF-R expression on B cells was increased in BD patients with vasculitis. Furthermore, in BD patients the ability to produce IgG and IL-6 (but not IL-10) was enhanced in BAFF-stimulated B lymphocytes. CONCLUSION: These results suggest that BAFF and its signalling in B cells contribute to B cell abnormalities and the development of skin disease in patients with BD.

Levels of IL-15 in serum and cerebrospinal fluid of patients with Behçet's disease.

Interleukin-15 (IL-15) is a novel proinflammatory cytokine, involved in the pathogenesis of inflammatory/autoimmune disease. The objective of our study was to measure serum and cerebrospinal fluid (CSF) IL-15 levels in patients with Behçet's disease (BD). CSF/serum IL-15 ratio was introduced to assess the origin of elevated IL-15 levels. We measured serum and CSF-IL-15 levels in 40 patients with BD (20 patients in active stage). Inflammatory and non-inflammatory neurological disease patients acted as controls. Active BD patients have significantly higher serum IL-15 levels (median 10.4 pg/ml; range 5.3-17.4) compared with BD in remission (6.05 pg/ml; 4-10.4) and healthy controls (4.65 pg/ml; 3.9-6.2). Similar serum IL-15 levels were found in active neuro-BD and inflammatory neurological disease (9.5 pg/ml; 5-13). Elevated levels of IL-15 were observed in CSF samples from neuro-BD patients (11 pg/ml; 8.5-15) and inflammatory neurological disease patients (10 pg/ml; 6.5-14) compared with patients with non-inflammatory neurological disease (4 pg/ml; 4-5.5; P < 0.001). Vascular cerebral BD lesions were associated with high CSF/serum IL-15 ratio. Our findings suggest that IL-15 is involved in BD inflammatory process, particularly in vasculitis foci, as an elevated CSF/serum IL-15 ratio characterizes vascular cerebral lesions.

CD4+CD25+ regulatory T cells in patients with Behçet's disease.

OBJECTIVE: To investigate whether the CD4+CD25+ regulatory T cell (Treg) population, which plays important role in autoimmune diseases is related to the pathophysiology of Behçet's disease (BD). METHODS: Forty-two patients with BD (20 patients in active disease) fulfilling the criteria of the International Study Group of BD. Twenty age-matched healthy controls were studied. We analyzed CD4+CD25+/high T cells and the mRNA expression of Foxp3, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and transforming growth factor beta (TGF-beta) in BD. We have studied the ability of CD4+CD25+ (Treg) to regulate proliferation of CD4+CD25- T cells during active BD stage. RESULTS: Active BD patients had significantly higher CD4+CD25+/high T cells, as compared with BD in the remission stage, and healthy controls. There was no significant differences in the CD4+ CD25+/high T cells expression between healthy controls and remission BD. In active BD, mRNA for Forkhead box p3 (Foxp3) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) were highly expressed when compared to remission BD and healthy controls. There was no differences in the mRNA expression for TGF-beta in active BD, remission BD and healthy controls. Functionally, CD4+CD25+/high T cells in active BD were impaired in their proliferative responses and could suppress the proliferation of their CD4+CD25- counterparts. CONCLUSION: These data demonstrate that CD4+CD25+ Treg cells, with the potential to regulate suppression of effector T cells, were increased in the peripheral circulation of active BD patients. The role of CD4+CD25+/high T cells in the regulatory process of the inflammation in active BD, could be taken in account.

Circulating soluble CD28 in patients with Behçet's disease: relationship to clinical manifestations.

OBJECTIVE: This study evaluates the presence of serum soluble CD28 (sCD28) in Behçet's disease (BD) and its relationship with clinical manifestations. METHODS: Soluble CD28 concentration was determined by ELISA in 120 patients with BD (80 patients in active stage), 60 patients with rheumatoid arthritis (RA) and 60 healthy subjects. RESULTS: Concentrations of sCD28 were significantly higher in patients with BD and RA than in healthy subjects. Patients with active BD expressed the highest level of sCD28 in serum. Soluble CD28 exhibited a drastic increase in active BD patients, compared to BD in remission. Soluble CD28 concentrations were higher in patients with active BD patients having vasculitis. Significant positive correlation was observed in a longitudinal study of 15 BD patients, between sCD28 and C-reactive protein. CONCLUSION: Our study suggests that fluctuations of sCD28 in BD reflects disease activity and should be assessed in evaluating disease activity.

Involvement of chemokines and Th1 cytokines in the pathogenesis of mucocutaneous lesions of Behçet's disease.

OBJECTIVE: To investigate a possible pathogenic role of cytokines in Behçet's disease (BD) by focusing on the analysis of cytokine gene expression within mucocutaneous BD lesions. METHODS: The study group comprised 20 patients with active BD. In this group, a set of chemokines as well as Th1 and Th2 cytokines in biopsy specimens obtained from oral and genital ulcers, pseudofolliculitis lesions, and lesions at the site of pathergy testing were studied using real-time quantitative reverse transcriptase-polymerase chain reaction. RESULTS: We observed important increases in the expression of interleukin-8 (IL-8) ( approximately 700-fold), monocyte chemoattractant protein 1 ( approximately 65-fold), interferon-gamma ( approximately 71-fold), and IL-12 ( approximately 69-fold) messenger RNA in BD lesions compared with normal skin. Except for IL-10 ( approximately 75-fold increase), Th2 cytokines (i.e., IL-4 and IL-13) were absent. CONCLUSION: Our data suggest a direct role of Th1 lymphocytes in the pathogenesis of mucocutaneous BD lesions.

Prolactin levels in Behçet's disease: no correlation with disease manifestations and activity.

OBJECTIVE: To assess prolactin level and its possible role in the pathogenesis and disease expression of patients with Behçet's disease (BD). MATERIALS AND METHODS: Twenty-eight patients with the diagnosis of Behçet's disease were selected. They all fulfilled the international criteria for BD. The control group consisted of 17 males and 6 females. Patients are divided into subgroups according to the clinical and paraclinical characteristics such as disease duration, ocular, articular and neurological involvement. Serum prolactin was measured by ELISA using Merck Kits on a Maggia 7000 Analyser. The normal range in males was<17ng/ml in males and<18ng/ml in females. The mean PRL level in each group and subgroup was calculated and compared with Student's t test. RESULTS: The mean prolactin level in the BD group (mean=13.76, SD=6.82), was higher than in the control group (mean=10.13, SD=5.46) with no statistically significant difference. The mean prolactin levels in all subgroups of patients with BD were higher than normal, but no statistically significant difference was shown between these subgroups. CONCLUSION: Hyperprolactinemia occurred in a small number of patients with BD and its significance remained unclear. Serum PRL level did not correlate with disease manifestations and activity.

[Behçet's disease associated with Crohn's disease]. / Association d'une maladie de Behçet et d'une maladie de Crohn.

INTRODUCTION: The association of Behçet's disease and of Crohn's disease is exceptional, and raises a nosological problem. CASE REPORT: A 24 year-old female developed since 1996 chronic diarrhea, abdominal pain, recurrent oral and genital ulcer and polyarthralgia. Endoscopic colonoscopy examination showed a diffuse colitis. Histological examination revealed epitheloid granuloma without vasculitis compatible with a Crohn's disease. The patient was treated with oral prednisone (1mg/kg/day). In November 1998, she was admitted for diarrhea. Many pseudofolliculitis lesions, uveitis and positive pathergy test were noted. The HLA was B 51. The diagnosis of Crohn's disease associated with Behçet's disease was made. She was treated with high doses of prednisone (1mg/kg/day and 6 monthly intravenous pulses of cyclophosphamide). Skin lesions and diarrhea improved within few days, and cleared completely within five months. Presently, the patient remains clinically free of disease. CONCLUSION: While being of different pathogenic origin, Behçet's disease and Crohn's disease may coexist within one and the same patient and cause diagnostic and therapeutic problems.

[Vena cava thrombosis in Behçet's disease. Analysis of a series of 10 cases]. / Thromboses caves dans la maladie de Behçet. Analyse d'une série de 10 observations.

AIM: To study the clinical characteristics and the evolution of vena cava thrombosis (VCT) in Behçet's disease (BD), as well as their association with other severe symptoms. PATIENTS AND METHODS: Among 121 BD, we selected those with VCT. All patients fulfilled the diagnostic criteria of the international study group of Behcet's disease. Different clinical and paraclinical parameters were determined and compared with the remaining group of patients (not having VCT) with chi 2 test with Yates' correction. Protein C, protein S and antithrombin III and anticardiolipin antibody (aCL) levels were measured in 9 patients; anti-beta 2-glycoprotein I antibodies (a beta 2GPI) were determined in 3 patients. RESULTS: Ten patients had a vena cava thrombosis (8.2%). They were all male with an average age of 35 years (range: 30-42). We had 3 cases of superior vena cava thrombosis, 6 cases of inferior VCT, and one case of both. The average delay to diagnosis of the VCT from the date of the BD diagnosis was 4.5 years (range: 6 months-14 years), and in one case the thrombosis revealed the disease. All patients were clinically symptomatic and the installation of the symptoms were progressive and insidious in all cases. Six patients had Budd-Chiari syndrome and 4 had a phlebitis of a lower limb. Among all the clinical characteristics studied, only neurological manifestations was significantly higher in patients with VCT (p = 0.001). Protein C, protein S and antithrombin III levels were normal in all cases. One patients was positive for IgG aCL and no patient was positive for a beta 2GPI. All our patients were treated by anticoagulation therapy and high-dose prednisone combined with intravenous cyclophosphamide in 5 cases. One patient died due to liver failure. The 9 others are clinically improved (6 cases) or stable (3 cases) after an average 2.5 year course.

Morphological evidence for a direct projection of trigeminal nerve fibers to the primary gustatory center in the sea catfish Plotosus anguillaris.

The central projections of the ramus mandibularis were examined in the Japanese sea catfish, Plotosus anguillaris by using the technique of transganglionic tracing with horseradish peroxidase (HRP). This ramus receives fibers from both the trigeminal and facial nerves and supplies primarily the two mandibular barbels. Two pathways for a direct trigeminal projection to the facial lobe (FL) were found: one from the main descending root of the Vth nerve (MRDV) to the medial portion of the FL, approximately midway between the rostro-caudal axis of the FL and a second, from deep RDV to the intermediate nucleus (NIF), beneath the medial lobule of the FL. The facial fibers project exclusively onto the medial portion of the FL and the NIF. The results show that fibers of these two cranial sensory nerves supplying the mandibular barbels converge centrally on the medial portion of the FL, indicating that the FL of the Japanese sea catfish is a highly differentiated center for both gustation and somatosensation.